DE60105689T2 - Process for the preparation of the mesylate trihydrate salt of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol - Google Patents

Description

aus deren D-(-)-Tartratsalz.The present invention relates to a process for the preparation of the mesylate trihydrate of the compound (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol Formula (I):

from their D - (-) - tartrate salt.

The Compound of the formula (I), (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol, shows a potent activity as an NMDA (N-methyl-D-aspartic acid) receptor antagonist and is useful in the treatment of epilepsy, anxiety, cerebral ischemia, muscle spasms, multi-infarction related Dementia, traumatic brain injury, pain, AIDS-related dementia, hypoglycemia, Migraine, amyotrophic lateral sclerosis, drug and alcohol dependence, Drug and alcohol withdrawal symptoms, psychotic conditions, urinary incontinence and degenerative changes of the central nervous system (CNS), such as Stroke, Alzheimer's Disease, Parkinson's disease and Huntington's disease.

The Mesylate trihydrate form of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol is more active than anhydrous mesylate because of its properties superior therapeutic agent. The mesylate trihydrate has a more stable crystal form than the anhydrous one Mesylate salt and, accordingly, a much longer shelf life. Because of the Inclusion of water in the crystal is subject to the trihydrate also less a loss of its crystal structure.

The US Pat. No. 6,008,233 describes the mesylate salt trihydrate which anhydrous mesylate salt, and the free base of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol and method for its production.

Farther is issued in U.S. Patent No. 5,185,343 issued February 9, 1993 was, in generic form on the free base, the anhydrous mesylate and to methods for their preparation. On their use for the treatment of some of the above mentioned disorders specifically in U.S. Patent No. 5,272,160, issued December 21, 1993 was granted; and in International Patent Application PCT / IB 95/00380, which designates the United States, filed on 18 May 1995 and WO 96/06081 was published.

their Use along with a compound that is capable of Balance of excitatory feedback from the ventral-lateral Nucleus of the thalamus in the cerebral cortex for the treatment of Parkinson's To improve and thus restore disease will be in the international Patent Application PCT / IB 95/00398, which names the United States, filed on 26 May 1995 and published as WO 96/37226, described.

SUMMARY THE INVENTION

welches die Verfahrensschritte
(i) Lösen des D-Tartratsalzes von (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol in einer wässrigen Methansulfonsäure-Lösung und
(ii) Abscheiden lassen des Methansulfonat-trihydratsalzes aus der Lösung.The present invention relates to a process for preparing the methanesulfonate trihydrate salt of the compound (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1- Propanol (I):

which the process steps
(i) dissolving the D-tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol in an aqueous methanesulfonic acid solution and
(ii) separating the methanesulfonate trihydrate salt from the solution.

In above method is the molar ratio of methanesulfonic acid to D - (-) - tartrate salt the compound (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol preferably in the range of 1.3 to 1.0. More preferred is the range the molar ratio of methanesulfonic acid to D - (-) - tartrate salt the compound (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol in the range of 1.10 to 1.05; most preferably, it is in the range from 1.10 to 1.08.

in the Process of the present invention will be the aqueous methanesulfonic acid solution of Step (i) preferably using pyrogen-free water produced.

in Gegenwart von D-(-) Weinsäure in wässrigem Methanol enthält und
(ii) Abtrennenlassen des (D)(-)-Tartratsalzes von (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol aus der Lösung.The present invention is also directed to one of the above-described processes for preparing the methanesulfonate trihydrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1 Propanol which further comprises the following steps:
(i) dissolving a racemic mixture containing the compounds of formula (I) and (II)

in the presence of D - (-) tartaric acid in aqueous methanol and
(ii) separating the (D) (-) - tartrate salt from (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol from the solution ,

In This method has the aqueous Methanol preferably has a water content of 5 to 20%. preferred is a variant in which the aqueous Methanol has a water content of 7 to 10%.

DETAILED DESCRIPTION OF THE INVENTION

The Mesylate salt trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol is a white one crystalline solid containing a single crystalline form and a good solubility in water (25 and 15 mg / ml in pH 3 and 7 buffered aqueous Solutions) having. Mesylate salt trihydrate is known to be from the anhydrous salt in an environment of 81% relative humidity forming an equilibrium. Earlier types of production of the Trihydrate of Mesylatsalzes, z. B. gem. US Patent No. 6,008,233, required the use of the free base as starting material, which in turn is the special step of insulation and drying the free base of the compound of formula I in the overall synthesis after separation of the enantiomers.

The However, the present invention allows the preparation of the trihydrate of the mesylate salt directly from the (D) - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol without the detour over the free base. The (D) - (-) - tartrate salt, as described above is a product of the enantiomeric resolution of racemic 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol. Accordingly allowed the present invention provides a much more efficient synthesis the mesylate salt with fewer process steps.

The Method of the present invention further comprises an improvement of the process for resolving the D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol. earlier Method, for. B. according to US patent No. 6,008,233, for the resolution of the racemate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol involved selective crystallization with optically active Tartrate salts of absolute methanol and then almost required always re-slurrying and / or recrystallizing to an acceptable purity of the enantiomers (1S, 2S) of 97% or better. The present invention thus provides a means to avoid repeated cleaning steps and greater efficiency to reach the entire synthesis path.

The the following reaction scheme is explained the process of the present invention:

Scheme 1:

Referring to Scheme 1, the racemic benzyl-protected ketone compound of formula (III) is treated either with NaBH ₄ in ethanol for 6-7 hours at 40-50 ° C or with potassium selecide (CalSelect K) in tetrahydrofuran for 1-2 hours at 10-20 ° C or, with any other useful reagents known to those skilled in the art, subject to reduction conditions to obtain a mixture of threo and erythro isomers, wherein the threo isomer predominates in a ratio of 80:20 or better in the crude reaction mixture

The solvent Methanol or THF should not contain noticeable amounts of water, that is, not contain more than 0.2 to 0.5% water. After the completed Isolation from the solvent For example, a product with nearly 90% threo orientation, i. in the form of the threo component as a racemic mixture of formula (IVA) (i.e., IVA-1 and IVA-2) to be obtained. The starting material of the formula (III) is after a method described in US Patent No. 6,008,233 (supra) receive.

Regarding scheme 2, the benzyl group from the racemate of the threo compound of Formula (IVA) by any means known in the art, preferably under hydrogenolysis conditions, most preferably by means of palladium / carbon in the presence of hydrogen in humid tetrahydrofuran, about 5 to 6 hours at 45 to 50 ° C away. Other effective means of removing the benzyl group As in the present case, those trained in this field Specialist known.

Scheme 2

The Product of the above reduction reaction, the racemic mixture of Antipodes of the formula (I) and (II) is then purified by means of formation and selective crystallization of the D - (-) - Tartratsalzes separated. The D - (-) - tartrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol (VA) is obtained directly from a solution of the racemate (I and II) in absolute methanol by heating the methanolic solution at about 50 to 55 ° C and slowly adding a solution of D - (-) - tartaric acid made in water. The mixture is then heated to about 60 to Heated to 65 ° C. and, if desired, a small amount of the D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol (VA); to facilitate the formation of the D - (-) - tartrate salt. The mixture will be about four hours at reflux temperature (60 to 65 ° C) held, being a viscous Suspension forms. The slurry is slowly cooled, and the solid is separated by filtration and washing with methanol. This procedure yields the D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol with 2% or less enantiomeric or diastereomeric impurities. The relationship from water to methanol should be adjusted so that the final solution in the Range of 5 to 20%, preferably 7 to 10%, water / methanol. Table 1 gives the clear improvement of the enantiomeric purity of D - (-) - tartrate salt again, when aqueous methanol compared to absolute Methanol as solvent used. When using absolute methanol as a solvent needed as shown in Table 1, up to two reslurries or recrystallization steps to a similar enantiomeric purity of the D - () - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol receive.

Table 1 Separation of the racemate (compounds I and II) with D - (-) - tartaric acid in methanol over aqueous methanol.

The Separation of the racemic 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol in aqueous Methanol over the D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol, essentially free of corresponding (1R, 2R) and others diastereomeric isomers is shown in Example 1. The Example 2 includes the method of use for comparison of absolute methanol as a solvent.

Scheme 3

According to the scheme 3 becomes the trihydrate of the mesylate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol directly from the D - (-) - tartrate salt by dissolving it in Water in the presence of 1.00 to 1.15, preferably 1.05 to 1.10 molar equivalents methane, by heating the mixture to about 60 to 65 ° C and then filtration the solution to remove any foreign solids. The heated solution becomes then slowly to 15 to 20 ° C cooled, being a thick one white Receives emulsion, further cooled to 0 to 5 ° C and then at 0 to 5 ° C granulated for one hour. After isolation of the product by filtration this is washed with cold water (0 to 5 ° C) and the mesylate salt then in an inert atmosphere dried. Table 2 explains the preparation of the trihydrate of Mesylatsalzes carried out under Variation of the ratio the molar equivalents of methanesulfonic acid to (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol.

Table 2. Preparation of a compound of formula VI from a compound of formula VA

The Trihydrate of Mesylatsalzes has, similar to the anhydrous Mesylate and the free base, a selective neuroprotective activity, on his anti-ischemic activity and his ability excitatory amino acid receptors to block is based. The preferred method, the neuroprotective activity To evaluate this connection is that of Ismail A. Shalaby et al., J. Pharm. Exper. Ther., 260, 925 (1992). This article is described below.

Cell culture. Hippocampus cells from 17-day-old rat fetuses (CD, Charles River Breeding Laboratories, Inc., Wilmington, Mass.) Were exposed to PRIMARIA culture plates (Falcon Co., Lincoln Park, NJ) for 2 to 3 weeks in serum-containing minimal medium containing non-essential amino acids containing 2 mM Glutamine, 21mM glucose, penicillin / streptomycin (5000 units each), 10% fetal bovine serum (1-7 days) and 10% horse serum (1-21 days). Cells were plated either on 96-well microtiter plates at a density of 80,000 cells per well or on 24-well culture plates at a density of 250,000 cells per well. The cultures were grown at 37 ° C in a tissue culture incubator with humidified CO ₂ at a level of 5% CO ₂ /95% air.

The Proliferation of non-neuronal cells is from the 6th to the 8th day culture by adding 20 μM uridine and 20μM % 5-fluoro-2-deoxyuridine (Sigma Chemical Co., St. Louis, Mo.). The culture medium is replaced every 2 to 3 days by fresh stock material replaced.

Glutamate toxicity. The cultures were tested for glutamate toxicity 2 to 3 weeks after the first plating. The culture medium was removed and the cultures were washed twice with CSS (in mmol): NaCl, 12-; KCl, 5.4; MgCl ₂ , 0.8; CaCl ₂ , 1.8; Glucose, 15; and 4- (2-hydroxyethyl) -1-piperazine-ethanesulfonic acid, 25 mM (pH 7.4). The cultures were then exposed to various glutamate concentrations for 15 minutes (37 ° C). After this incubation, the cultures were rinsed three times with glutamate-free CSS and twice with fresh culture medium without serum. The cultures were then incubated in serum-free culture medium for 20 to 24 hours. The compounds to be tested are added 2 minutes before and during the 15 minute contact with glutamate. In some experiments, the compound is added at various times after contact with glutamate and during the following 20 to 24 hours.

The viability of the cells is routinely checked 20 to 24 hours after the addition of excitotoxin by measuring the activity of the cytosolic enzyme LDH. The LDH activity is determined in the culture medium from each of the 96 wells of the microtiter plates. A 50 μl sample of the medium is added to the same volume of sodium phosphate buffer (0.1 M, pH 7.4) containing 1.32 mM sodium pyruvate and 2.9 mM NADH. The absorbance of the complete reaction mixture at 340 nm is monitored for each of the 96 wells every five seconds for two minutes by a microtiter plate automatic spectrophotometric reader (Molecular Devices, Menlo Park, Calif.). The absorption rate is determined by means of an IBM SOFT max program (version 1.01, Molecular Devices) is automatically calculated and used as an index of LDH activity.

The Morphological determination of neural viability is by means of phase contrast microscopy carried out. The 96-well culture plates do not leave good phase contrast images too, so be for this the cells cultured on 24-well plates were used. Both culture plates are the same in terms of quantitative glutamate toxicity sensitive and show up to 0.1 to 24 hours after exposure 1.0 mM glutamate gives a two- to threefold increase in LDH activity.

reagents: DTG may be purchased from the Aldrich Chemical Company (Milwaukee, Wis.) And Haloperidol purchased from Research Biochemicals Inc. (Natick, Mass.) become. Spermin may be purchased from Sigma Chemical Co. (St. Louis, Mo.). be acquired. Horse serum and fetal bovine serum can be obtained from Hyclone (Logan, Utah). Culture media, glutamine and penicillin / streptomycin are commercially available from Gibco Co. (Grand Island, NY.).

Data analysis: Neurotoxicity can be quantified by measuring the activity of LDH present in the culture medium 20 to 24 hours after glutamate exposure. The increased LDH activity in the culture medium correlates with the breakdown and degeneration of neurons (Koh and Choi, 1987). Because the actual LDH values of different cultures vary, data are routinely expressed in relation to buffer treated sibling wells of the same plate culture. In order to obtain an index of the LDH activity of glutamate- and drug-treated cultures, the LDH values of control cultures are subtracted from those of the treated groups. The data for the treatment with drugs are expressed in each experiment as a percent-induced LDH increase by 1 mM glutamate (or NMDA). Concentrations of NMDA antagonists needed to abolish 50% of the excitotoxin (IC ₅₀ ) -induced LDH increase are determined by log-probit analysis from the pooled results of three independent experiments.

The selective neuroprotective, antiischemic and excitatory amino acid blocking agents Properties of the trihydrate of the product prepared according to this invention Mesylate salt gives its utility for the Treatment of pathological conditions, selected from degenerative states of the CNS, e.g. Stroke, Alzheimer's, Parkinson's and Huntington's disease, epilepsy, anxiety, cerebral ischemia, Muscle spasms, dementia after multiple infarction, traumatic brain injuries, Pain, AIDS-related dementia, hypoglycaemia, migraine, amyotrophic lateral sclerosis, Drug and alcohol dependence, Drug- and alcohol-related withdrawal symptoms, psychotic states and urinary incontinence.

at the systemic treatment of such conditions, the dosage is typical at 0.02 to 250 mg per kg per day (0.001 to 12.5 g per day at a typical person of 50 kg weight) in single or divided Dosages, independent on the type of application. A more preferred dosage range is about 0.15 mg per kg and day to about 250 mg per kg and day. Of course, the attending physician may dependent of the particular type of the disease and the condition of the patient Dosages outside be prescribed to this area. Oral administration is generally preferred. However for the case that the patient is unable to swallow, or if the oral application is otherwise impeded, the (preferred) parenteral (i.m., i.v.) or topical application is preferred.

The Trihydrate of the mesitylate salt may be in the form of pharmaceutical compositions in association with a pharmaceutically acceptable carrier or solvent be applied. Such compositions are basically incorporated in Conventional way by means of solid or liquid carriers or solvents formulated as the desired Type of application requires: for oral administration in the form of tablets, hard or soft gelatine capsules, Suspensions, granules, powder or similar, for parenteral administration in the form injectable solutions or suspensions or the like and for topical application in the form of solutions, lotions, ointments, balm etc.

The following examples illustrate the methods of the present invention. The melting points are not corrected. NMR data are reported in parts per million (δ) and refer to the deuterium lock signal of the solvent used [perdeuterodimethylsulfoxide (d ₆ -DMSO) unless otherwise stated.] Commercial reagents were used without further purification.

EXAMPLE 1

Separation of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol using of D - (-) - tartaric acid in watery methanol

Racemic 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol (78.0 kg, 207.7 moles) and absolute methanol (1.223 liters) were made into a clean Reactor under nitrogen atmosphere. The mixture was stirred and heated to 50-55 ° C. After the solution was held at 50 to 55 ° C for one hour, a solution of D - (-) - tartaric acid (32.1 kg, 214 mol) in water (105 L) was added over 10 minutes. The solution was heated to 60-65 ° C and 50 grams of the D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl ) -1-propanol in methanol (0.5 L) was added. The solution was refluxed for four hours (60-65 ° C) to form a viscous suspension. The slurry was cooled to 30 to 35 ° C over one and a half hours and then filtered off at 30 to 35 ° C. The cake was washed with methanol (204 L) and then dried in vacuo at 40 to 45 ° C for 20 to 30 hours. The D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol (39.4 kg) was prepared in a yield of 40 wt.% (80% of theory). [α] _D ²⁵ + 35.2 (0.0185, water). Chiral HPLC analysis revealed that the solid contained 1.2% of the (1R, 2R) enantiomers and 0.8% of the (1R, 2S) and (1S, 2R) diastereomers.

EXAMPLE 2

Separation of 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol using of D - (-) - tartaric acid in absolute methanol

In become a suitable and kept under nitrogen atmosphere vessel 1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol (189.5 g, 0.58 mol) and methanol (3.8 l). The mixture was at 50 to 55 ° C heated then D - (-) - tartaric acid (87.0 grams, 0.58 moles). The mixture was submerged for 5 hours backflow (~ 65 ° C) heated. The slurry was cooled to 30 to 35 ° C and then granulated for one hour at 30 to 35 ° C. The product was filtered and the cake washed with fresh methanol (135 ml). The wet cake was sampled for chiral HPLC taken to determine the degree of enantiomeric impurities. The wet cake was suspended in methanol (1.6 L) and the resulting slurry under reflux (65 ° C) below nitrogen atmosphere five hours heated. The slurry was at 30 to 35 ° C cooled, for one hour at 30 to 35 ° C granulated and then filtered off. The filter cake was washed with methanol (136 ml) and then in vacuo for 18 to 24 hours at 40 up to 45 ° C dried. A sample was analyzed by chiral HPLC. The D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol (118.0 g) was obtained in 43% yield. Sometimes is, As the results in Table 1 above show, another reslurrying into Methanol required to quantitatively (1R, 2R) enantiomeric impurities reduce it by less than 2.5%.

EXAMPLE 3

Preparation of trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol-mesylate

The D - (-) - tartrate salt of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenyl-piperidin-1-yl) -1-propanol (5.0 g, 10, 5 mmoles), water (17.5 ml) and methanesulfonic acid (1.05 grams, 11.0 mmoles) were combined in a 50 ml three-necked flask under nitrogen atmosphere. The slurry was heated to 60-65 ° C and the resulting solution was filtered. The filtrate was slowly cooled to 15 to 20 ° C over one hour until a thick white suspension was obtained. The slurry was further cooled to 0 to 5 ° C and then granulated at 0 to 5 ° C for one hour. The product was filtered off, the cake washed with 2.5 ml of cold water (0-5 ° C) and then dried at 20-25 ° C under nitrogen gassing. The trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol mesylate (4.53 g) was obtained in an overall yield of 90 , 4% recovered as a white crystalline solid. The physical and chemical properties of the isolated trihydrate were identical to an authentic sample.
¹ H NMR (d ₆ -DMSO) δ 9.58 (s, 1H), 8.91 (S, 1H), 7.48 (m, 2H), 7.35 (m, 2H), 7.21 (m, 3H), 6.77 (d, J = 8.5 Hz, 2H) 6.35 (s, 1H), 5.52 (s, 1H), 4.58 (d, J = 8.1 Hz, 1H), 3.40 (m, 11H), 2.63 (m, 1H), 2.3 ( s, 3H), 1.78 (m, 2H), 0.95 (d, J = 6.6 Hz, 3H). ¹³ C NMR (d ₆ -DMSO) δ 158.13, 148.61, 132.27, 129.27, 128.80, 127.51, 125.26, 115.89, 72.12, 68.89, 66.30, 47.40, 42.91, 35.71, 35.37. Analysis calculated for:
C ₂₀ H ₂₅ NO ₃ .CH ₃ SO ₃ H.3H ₂ O: C, 52.81; H, 7.39; N, 2.93; S, 6.71. Found: C, 52.77; H, 7.50; N, 2.94; S, 6.96. α _D = + 54.5 ° (anhydrous basis).

If in the above method low-pyrogenic water under pyrogen-free The trihydrate of (1S, 2S) -1- (4-hydroxyphenyl) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -1-propanol mesylate is used suitable for the production of parenteral pharmaceutical preparations. Table 2 gives the preparation of the trihydrate using different equivalents of methanesulfonic acid again. It is notable that when using low equivalents of methanesulfonic acid (1.0 to 1.05) the trihydrate product is cloudy when dissolved in water Residues (traces insoluble Substances), which is an unacceptable property for parenteral Represents formulations.

Claims (8)

A process for preparing the methanesulfonate trihydrate salt of a compound of formula (I):

comprising the steps of (i) dissolving the D - (-) tartrate salt of the compound of formula (I) in an aqueous solution of methanesulfonic acid; and (ii) allowing the methanesulfonate trihydrate salt to separate from the solution. A method according to claim 1, wherein the molar ratio of methanesulfonic acid to the D - (-) - tartrate salt of the compound of formula (I) in the range from 1.3 to 1.0. A method according to claim 1, wherein the molar ratio of methanesulfonic acid to the D - (-) - tartrate salt of the compound of formula (I) in the range from 1.10 to 1.05. A method according to claim 1, wherein the molar ratio of methanesulfonic acid to the D - (-) - tartrate salt of the compound of formula (I) in the range from 1.10 to 1.08. A method according to claim 1, wherein the aqueous methane is produced by means of pyrogen-free water. A method according to claim 1, further comprising the steps of (i) dissolving a racemic mixture of the compounds of formulas (I) and (II)

in aqueous methanol in the presence of D - (-) - tartaric acid; and (ii) allowing the solution to dissociate the D - (-) tartrate salt of the compound of formula (I). A method according to claim 6, wherein the aqueous Methanol has a water content of 5 to 20%. A method according to claim 6, wherein the aqueous Methanol has a water content of 7 to 10%.